Genetics of human isolated hereditary nail disorders

Genetics of human isolated hereditary nail disordersBritish Journal of Dermatology
Genetics of human isolated hereditary nail disorders S. Khan,1,2 S. Basit,3 R. Habib,4 A. Kamal,1 N. Muhammad1 and W. Ahmad5
1Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat 26000, Khyber Pakhtunkhwa, Pakistan 2Genomic Core Facility, interim Translational Research Institute (iTRI), Academic Health System, Hamad Medical Corporation, 3050 Doha, Qatar 3Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, 30001 Almadinah Almunawarah, Saudi Arabia 4Department of Biosciences, COMSATS Institute of Information Technology, Park Road, Islamabad 45600, Pakistan 5Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan
Linked Comment: Betz, Br J Dermatol 2015; 173: 886.
Correspondence
E-mails: [email protected] and
DOI 10.1111/bjd.14023
Summary
Human hereditary nail disorders constitute a rare and heterogeneous group of ectodermal dysplasias. They occur as isolated and/or syndromic ectodermal con- ditions where other ectodermal appendages are also involved, and can occur associated with skeletal dysplasia. ‘Nail disorder, nonsyndromic congenital’ (OMIM; Online Mendelian Inheritance in Man) is subclassified into 10 different types. The underlying genes identified thus far are expressed in the nail bed and play important roles in nail development and morphogenesis. Here, we review the current literature on nail disorders and present a coherent review on the genetics of nail disorders. This review will pave the way to identifying putative genes and pathways involved in nail development and morphogenesis.
Nails are specialized epithelial miniorgan structures designed
to protect the soft tissues of the distal digits of the fingers and
toes from environmental assault and injury. In addition to this
basic function, the nail apparatus – a modified ectodermal
appendage – contributes to the sensory perception of finger-
tips, fine manipulation of small objects with refined dexterity,
is a tool for scratching and grooming, and can be utilized as a
natural weapon. Finally, well manicured, embellished nails
can enhance the aesthetic appeal of the hands and feet.
Human nail development starts around the ninth week of
gestation and is completed during the fifth month of preg-
nancy, with development of the toenails lagging approxi-
mately 4 weeks behind the fingernails.1 Nail is produced by
the matrix and grows over the nail bed. The mature nail plate
grows continuously through life as a result of matrix epithelial
cell differentiation, and consists of a number of hard and soft
keratin molecules embedded in an amorphous matrix.
Inherited anomalies of nail are rare and represent a hetero-
geneous group of genodermatoses. Nail disorders can occur as
rare isolated conditions or as a part of ectodermal syndromes
involving anomalies in other epidermal appendages (e.g. hair,
teeth and sweat glands) and skin, or are associated with skeletal
deformity. Most inherited nail disorders manifest either with
nail hypertrophy or nail hypoplasia.2 Nail hypertrophy includes
pachyonychia congenita type 1 [Online Mendelian Inheritance
in Man (OMIM) 167200], type 2 (OMIM 167210), type 3
(OMIM 615726) and type 4 (OMIM 615728), which are
caused by mutations in KRT16 (OMIM 148067), KRT17 (OMIM
148069), KRT6A (OMIM 148041) and KRT6B (OMIM 148042),
respectively. Nail patella syndrome and isolated congenital nail
dysplasia are examples of nail hypoplasia disorders.
Defects in genes involved in nail development/homeostasis
are underlying causes of nail abnormalities. Disruption in the
normal process of dorsoventral patterning of the distal limb
also upsets nail development.3 Despite considerable advances
in the diagnosis and management of nail disorders, knowledge
of the molecular developmental pathways of nail growth and
morphogenesis is relatively limited. The molecular basis of
some nail disorders has only been elucidated during the last
few years.
This review is an account of recent updates in the genetics
of ‘nail disorder, nonsyndromic congenital’ (NDNC), which
are classified in the literature into 10 different types and
included in OMIM. These are described in the following sec-
tions along with the available information on the genetic
defects associated with them.
NDNC-1 (OMIM 161050) is also termed ‘twenty nail dystro-
phy’ (TND) or trachyonychia. It is characterized by excessive
longitudinal striations and numerous superficial pits on the
nails, which have a distinctive rough, sand paper-like appear-
ance. Nails are variably involved and may show thinning,
thickening, pitting, ridging, koilonychias, opalescence and loss
of lustre, or may be spared.4 NDNC-1 segregates in an autoso-
mal dominant manner.
At least three familial cases and one sporadic one showing
NDNC-1 phenotypes have been reported. The various pheno-
types observed include the absence of thumb nails; thin, frag-
ile nails split at the ends; longitudinal ridges; ragged distal
edges; and discolored TND.5–8 To date, the gene/loci causing
NDNC-1 is unknown.
NDNC-2 is described in the literature as koilonychia or spoon-
shaped nails. This is a very rare disease in which the nails are
abnormally thin and concave from side to side, with turned up
edges. The mode of inheritance of NDNC-2 is dominant.
To date, three families showing typical features of koilony-
chias of fingernails and toenails have been reported.9–11 The
gene/loci underlying NDNC-2 is yet to be discovered.
Nail disorder, nonsyndromic congenital, 3
NDNC-3, or leuconychia, is the most familiar form of nail
discoloration abnormality, marked by white discoloration of
the nails (Fig. 1). Based on the distribution of the white tone,
leuconychia is classified into three different types: (i) true leu-
conychia, with the involvement of the nail plate originating in
the matrix; (ii) apparent leuconychia, involving subungual tis-
sue; and (iii) pseudoleuconychia, when the matrix is not
responsible for the nail plate alteration. True leuconychia is
further separated into total and subtotal or partial, the latter
occurring as leuconychia punctata, leuconychia striata and leu-
conychia distal.12 The inheritance patterns of hereditary
leuconychia can be both autosomal recessive and dominant.13
Leuconychia (OMIM 151600) was mapped to chromosome
3p21.3-p22 with pathogenic mutations in PLCD1 (OMIM
6022142), detected in several Pakistani families, inherited
both in autosomal dominant and recessive fashion.13 Affected
individuals had chalky white nails (complete leuconychia)
along with translucency and yellowish coloration in the distal
parts of the nail plate (incomplete leuconychia).13,14
To date, two mutations in families showing autosomal
dominant inheritance and four mutations in isolated families
showing a recessive mode of inheritance have been reported
(Table 1).13–15
PLCD1 consists of 15 exons, spanning 2217 kb and encodes
two isoforms containing 777 and 756 amino acids, respec-
tively. Phospholipase C, d1 is a member of a large superfamily
of phosphoinositide-specific phospholipase C (PLC) enzymes,
which are involved in the hydrolysis of phosphatidylinositol
4,5-bisphosphate to produce second messengers including dia-
cylglycerol and inisitol triphosphate (IP3). Disruption of PLCD1
results in a significant reduction of inositol monophosphate, a
downstream metabolite of IP3.13 High expression of PLC-d1 has been reported in nail matrix, hair follicles, hair matrix and
the nail bed.13,16
keratin gene expression, essential for nail differentiation.17
Interestingly, loss-of-function mutations in FOXN1 result in
defects of onycholemmal differentiation and severe ony-
chodystrophy in mice and humans.18 Therefore, loss of PLC-
d1 function may result in abnormal keratinization of the nail
plate owing to aberrant expression of hard keratins causing
the leuconychia phenotype.
Complete absence or severe hypoplasia of all fingernails and
toenails without significant bone anomalies is the characteristic
feature of NDNC-4 (OMIM 206800), also termed anonychia/
hyponychia congenita. Hyponychia is the milder phenotypic
variant of anonychia. Isolated anonychia is a rare dysplasia that
usually follows autosomal recessive inheritance with variable
expression, even within members of the same family.19
Affected individuals either show complete absence of the nail
Fig 1. Clinical presentation of an individual with leuconychia
showing white discoloration of the nail plate, involving all 20 nails.
Note yellow pigmentation of the second nail of the right toe (nail
disorder, nonsyndromic congenital, 3).
© 2015 British Association of Dermatologists British Journal of Dermatology (2015) 173, pp922–929
Genetics of human hereditary nail disorders, S. Khan et al. 923
plate and matrix, with only the nail bed present, or hypony-
chia, with some remnants of rudimentary, fragile nail plates
(Fig. 2).12,20
reported for isolated nail dysplasia.21,22 The encoded R-spon-
din (RSPO)4 protein acts as an agonist for the Frizzled (FZD)
family of receptors, which is involved in activation of the
Wnt/b-catenin signalling pathway that is crucial for the for-
mation of ectodermal appendages like nail.21
To date, 18 mutations in RSPO4 causing isolated anonychia/
hyponychia congenita have been identified in different popu-
lations of the world (Table 1).19–25 So far, no correlation has
been established between mutations detected in RSPO4 and the
specific phenotype observed.
The mammalian family of RSPO proteins includes four
independent gene products (RSPO1–RSPO4), which share 40– 60% pairwise amino acid sequence identity and similar
domain architecture.26 RSPO4 encodes a secreted protein of
approximately 35 kDa, containing 234 amino acids. Like other
Table 1 List of mutations so far reported in genes associated with hereditary nail disorders
Mutation cDNA Protein Effect Phenotype Reference
RSPO4
Missense c.194A>G p.Gln65Arg Aa substitution Anonychia Blaydon et al.21
Missense c.284G>T p.Cys95Phe Aa substitution Anonychia Blaydon et al.21
Missense c.319T>C p.Cys107Arg Aa substitution Anonychia Blaydon et al.21
Missense c.353G>A p.Cys118Tyr Aa substitution Anonychia Blaydon et al.21
Splice site c.IVS1 + 1G>A Skipping exon 1 FS + PTC Anonychia Blaydon et al.21
Splice site c.IVS1–1G>A Skipping exon 1 FS + PTC Anonychia Blaydon et al.21
Deletion c.95_110del16 p.Gly32fs* FS + PTC Anonychia Blaydon et al.21
Deletion c.9_+17del26 Loss of 16 Aa Truncated protein Anonychia Blaydon et al.21
Missense c.218G>A p.Cys73Tyr Aa substitution Anonychia Bergmann et al.22
Insertion c.92–93insG Leu31fs* FS + PTC Anonychia Bergmann et al.22
Missense c.3G>A p.Met1Ile Aa substitution Anonychia Ishii et al.20
Splice site c.IVS2-1G>A Skipping exon 2 FS + PTC Anonychia Ishii et al.20
Missense c.190C>T p.Arg64Cys Aa substitution Anonychia Br€uchle et al.19
Nonsense c.301C>T p.Gln101* PTC Anonychia Br€uchle et al.19
Missense c.199G>C p.Gly67Arg Aa substitution Anonychia Chishti et al.23
Missense c.178C>T p.Arg60Trp Aa substitution Anonychia Khan et al.24
Nonsense c.18C>A p.Cys6* PTC Anonychia Wasif and Ahmad25
FZD6
Missense c.1531C>T Arg511Cys Aa substitution Claw-shaped nail Fr€ojmark et al.48
Nonsense c.1750G>T Glu584* PTC Claw-shaped nail Fr€ojmark et al. and Naz et al.48,49
Missense c.1266G>A p.Gly422Asp Aa substitution Claw-shaped nail Raza et al.50
Missense c.1525C>T Arg509Ter Aa substitution Claw-shaped nail Wilson et al.51
Missense c.286C>T Arg96Cys Aa substitution Claw-shaped nail Wilson et al.51
Missense c.1312G>A Glu438Lys Aa substitution Claw-shaped nail Wilson et al.51
HPGD Missense c.577T>C p.Ser193Pro Aa substitution Nail clubbing Tariq et al.61
Missense p.Ala140Pro Nail clubbing Uppal et al.60
Insertion c.232_241delinsCA Nail clubbing Uppal et al.60
Deletion c.175delCT Nail clubbing Uppal et al.60
PLCD1 Missense c.625T>C p.Cys209Arg Aa substitution Leuconychia Kiuru et al.13
Nonsense c.1309C>T p.Arg437* PTC Leuconychia Kiuru et al.13
Missense c.1720C>T p.Ala574Thr Aa substitution Leuconychia Kiuru et al.13
Deletion c.1792-TGTAGTGGCC FS + PTC Leuconychia Kiuru et al.13
Duplication c.2220-2223dupAGAG FS + PTC Leuconychia Mir et al.14
c.1055G>A p.Ala285Glyfs*80 FS + PTC Leuconychia Farooq et al.15
COL7A1
Missense c.6946G>A p.Gly2316Arg Aa substitution Dystrophic toenails Shimizu et al.45
Missense c.6859G>A p.Gly2287Arg Aa substitution Dystrophic toenails Shimizu et al.45
Missense c.4783G>C p.Gly1595Arg Aa substitution Dystrophic toenails Sato-Matsumura et al.46
Missense c.5443G>A p.Gly1815Arg Aa substitution Dystrophic toenails Sato-Matsumura et al.46
Aa, amino acid; FS, frame shift; PTC, premature termination codon.
© 2015 British Association of DermatologistsBritish Journal of Dermatology (2015) 173, pp922–929
924 Genetics of human hereditary nail disorders, S. Khan et al.
RSPO proteins, RSPO4 contains an N-terminal signal peptide
encoded by exon 1 for secretion, followed by two furin-type
cysteine-rich domains encoded by exons 2 and 3, a throm-
bospondin-type domain encoded by exon 4 and a C-terminal
basic region that scores highly as a nuclear localization signal.
The furin-like repeats are believed to be required for activation
and stabilization of b-catenin.27
nalling, resulting in a wide range of biological processes such
as cell proliferation, differentiation, stem cell maintenance and
mature tissue homeostasis. Secreted RSPO proteins interact
synergistically with the Wnt family of ligands, causing activa-
tion of the canonical Wnt signal pathway induced by binding
of the Wnt ligands to FZD receptors and low-density lipopro-
tein receptor-related protein 5 or 6 (LRP5/6) co-receptors.28
As a consequence, it stimulates cytoplasmic accumulation and
translocation of the b-catenin protein to the nucleus. In the
nucleus, b-catenin associates with the T-cell factor (TCF)/lym-
phoid enhancer factor (LEF) transcription factor complex that
controls target gene activation.29,30 Recently, three reports
identified leucine-rich repeat-containing G-protein-coupled
receptor (Lgr)4, Lgr5 and Lgr6 as the receptors of the RSPO
proteins.31 The Lgr proteins are believed to be physically cou-
pled with the FZD/LRP complex. So the RSPO component in
Wnt signalling may consequently be mediated by the activated
FZD–LRP5/6 co-receptors.27
tips and nails are developed.20 Additionally, RPSO4 transcripts
have been identified in human primary fibroblasts but not in
keratinocytes. Hence, RSPO4 might function in the activation
of Wnt/b-catenin signalling during ectodermal–mesenchymal
crosstalk at the early stages of nail development.21 As the nail
bed is intact in affected individuals with RSPO4 mutations, it
has been suggested that RSPO4 might be involved in the
advanced stages of nail morphogenesis.32
Nail disorder, nonsyndromic congenital, 5
Hereditary distal onycholysis is grouped as NDNC-5 (OMIM
164800). It is characterized by a decreased growth rate, thick
and hard nails, and a straight or concave proximal edge of
detachment. The mode of inheritance of NDNC-5 is autosomal
dominant. In 1966, Schulze reported a family showing ony-
cholysis, slow nail growth, thick and hard nails.33 Some nails
also had increased transverse curvature and absent lunulae.
Several other families, of different ethnicities, reported as
showing dominant inheritance, had onycholysis, thickening
and discoloration of the finger- and toenails.34–36 The causa-
tive gene/loci for NDNC-5 is yet to be reported.
Nail disorder, nonsyndromic congenital, 6
Congenital absences of nails are of two types: (i) complete
and (ii) partial. Complete absences of nails were discussed ear-
lier and are categorized as NDNC-4. Partial absences of nails
are cases where the thumbs and big toes are more severely
affected, while the remaining digits are less affected. Such
cases of the partial absence of nails are referred to here as
NDNC-6 (OMIM 107000).
partial absences of nails. The mode of inheritance is dominant.
Several reports from different ethnic groups revealed anony-
chia of the thumbs and toenails, and onychodystrophy.
Abnormalities in the nails of digits other than thumbs and big
toes are of varying degrees of severity.37–41 The gene underly-
ing NDNC-6 has not been identified yet.
Nail disorder, nonsyndromic congenital, 7
NDNC-7 (OMIM 605779) is characterized by nails with longi-
tudinal streaks, thinning of the nail plate, poorly developed or
absent lunulae, along with variously disturbed formation of
the nail plate leading to increased vulnerability of the free nail
margins. The mode of inheritance is autosomal dominant.
NDNC-7 was described by Hamm et al.42 in a large German
family of 22 individuals. All 22 affected members have defects
in their toes and fingernails, which Krebsova et al.43 mapped
to chromosome 17p13. The candidate gene for this locus is
yet to be discovered.
Fig 2. An individual showing an anonychia phenotype. Note the
reduction in nail field size, absence of nail plates and swollen nail
matrix (nail disorder, nonsyndromic congenital, 4).
© 2015 British Association of Dermatologists British Journal of Dermatology (2015) 173, pp922–929
Genetics of human hereditary nail disorders, S. Khan et al. 925
Nail disorder, nonsyndromic congenital, 8
NDNC-8 (OMIM 607523) is also known as isolated toenail
dystrophy. Affected individuals show dystrophy of the toenails
only. The mode of inheritance of NDNC-8 is autosomal domi-
nant.
gous mutation (p.Gly1519Asp; p.Gly2251Glu) in a girl
affected by bullous dermolysis from this family; however, the
mother was a heterozygous carrier of the p.Gly2251Glu muta-
tion. Shimizu et al.45 reported a Japanese girl showing unusual
epidermolysis bullosa dystrophica, having compound
heterozygous missense mutations in COL7A1 (p.Gly2316Arg;
p.Gly2287Arg). The girl’s mother was affected by mild toenail
dystrophy without skin problems, and was a heterozygous car-
rier for the p.Gly2287Arg mutation. Her mother, maternal
uncle and maternal grandmother were also heterozygous
carriers of this mutation.
Two Japanese families with dystrophic toenails were stud-
ied. In affected members of the first family, the nail plates of
the toenails were buried in the nail bed, while the free edges
of the nail were deformed and narrow. In the second family,
a female patient had a shrunken big toenail, which was buried
in the nail bed and severely deformed. Sequencing of COL7A1
identified two missense mutations in both families.46
COL7A1 consists of 118 exons and is localized to chromo-
some 3p21.3. This gene encodes the alpha chain of type VII
collagen. The type VII collagen fibril is composed of three
identical a-collagen chains, which are restricted to the base-
ment zone beneath stratified squamous epithelium. The main
function of COL7A1 protein is to anchor the fibril between
the external epithelium and the underlying stroma.
Nail disorder, nonsyndromic congenital, 9
A Pakistani family with an isolated autosomal recessive form
of hereditary nail dysplasia (NDNC-9; OMIM 614149) has
been reported by Rafiq et al.47 At birth, all affected members
with the NDNC-9 phenotype had normal finger- and toenails.
By the age of 7–8 years, they started to show onychodystro-
phy of the fingers and toes, which differentially affected the
finger- and toenails (Fig. 3). Dystrophy of the finger- and
toenails started at the same time but led to anonychia on the
toenails and onycholysis on the fingernails. Through a gen-
ome-wide scan the NDNC-9 phenotype was localized to chro-
mosome 17q25.1-17q25.3.47 The candidate gene for this
locus is yet to be identified.
Nail disorder, nonsyndromic congenital, 10
In autosomal recessive nail dysplasia, affected individuals show
thick, hard nails on the hands and feet. In the main, nails are
shiny, hyperplastic and hyperpigmented from birth. A very
slow rate of nail growth has been observed in affected indi-
viduals, and trimming of the nails was required only at inter-
vals of a few years. At the age of about 10 years, the nails
develop into a claw-like structure, which might represent an
outgrowth from below the edge of the nail (NDNC-10; OMIM
614157) (Fig. 4).48,49
8q22.3,48 and sequence analysis of FZD6 (OMIM 603409)
revealed mutations in multiple families. To date, five
mutations have been reported in FZD6, including three mis-
sense, one nonsense and one compound heterozygous
(Table 1).48–51
FZD6 consists of eight exons, spanning 3719 kb, and
encodes a 706-amino acid protein of 80 kDa in size. Frizzled
class receptor (FZD)6 belongs to the heptahelical class of FZD
receptors characterized by an extracellular cysteine-rich
domain at the N-terminal region that forms the signal peptide
sequence, followed by seven transmembrane domains and an
internal PDZ-interacting motif at the C-terminal region neces-
sary for the recruitment of the phosphoproteins dishevelled
1–3 and other signalling factors, as well as for trafficking of
the receptor.
The FZD family of proteins, including FZD6, serve as recep-
tors for the Wnt ligand family. LRP5 and LRP6 serve as co-re-
ceptors with FZD proteins.52 The best-known signalling
pathway downstream of FZD is the canonical Wnt/b-catenin pathway, leading to the stabilization of b-catenin, nuclear
translocation and subsequent TCF/LEF-dependent transcription
of Wnt target genes.53 Besides Wnt–FZD signalling it has been
revealed that FZD6 has the ability to transduce the b-catenin- dependent WNT3A and b-catenin-independent WNT5A path-
ways.54 Wnt–FZD signalling is vital for numerous develop-
Fig 3. Individual with onychodystrophy, showing onycholysis of
fingernails and anonychia of toenails (nail disorder, nonsyndromic
congenital, 9).47
© 2015 British Association of DermatologistsBritish Journal of Dermatology (2015) 173, pp922–929
926 Genetics of human hereditary nail disorders, S. Khan et al.
mental processes such as tissue morphogenesis, differentiation
and regeneration in all animals.55
It has been shown that FZD6 is involved in the transcrip-
tional regulation of 63 genes essential for epidermal differenti-
ation, including keratins, keratin-associated proteins, and
transglutaminases and their substrates.56
Isolated congenital nail clubbing
Hereditary nail clubbing (or digital clubbing) is a distinct rare
genodermatosis entity characterized by enlargement of the nail
plate and terminal segments of the fingers and toes, resulting
from proliferation of the…